This program Project Grant (PPG) proposal comprises four Projects and two Cores. The focus of the projects is identification of molecular signaling that initiate fatal cardiac arrhythmias (Sudden Cardiac Death SCD). A central hypotheses is that adrenergic modulation of ion channels perturbs intracellular Ca signaling leading to triggers of SCD. We propose that perturbations of intracellular calcium homeostasis, primarily due to defective regulation of the ion channels including potassium, sodium, calcium channels as well as the ryanodine receptor/calcium release channel on the cardiac sarcoplasmic reticulum, initiate, initiate triggers of fatal cardiac arrythmias. Each of the proposed projects requires extensive work with animal models which will be supported by the following core. The present core will provide support for the projects in four major areas: (a) the preparation and maintenance of transgenic and knockout mice and (b) Characterization of transgenic and knock-out mice including preparation and analysis of tissue specimens from animals (c) Physiological measurements on transgenic and knockout mice including drug testing and (d) Characterizing B adrenergic receptor signaling in the normal and transgenic mouse hearts.